HBV infection, particularly chronic HBV infection is one of the most important public sanitation problems globally (Dienstag J L. Hepatitis B virus infection. N Engl J Med 2008 Oct. 2; 359(14):1486-1500). Chronic HBV infection may cause a series of liver diseases such as Chronic hepatitis B (CHB), Liver cirrhosis (LC) and Hepatocellular carcinoma (HCC) (Liaw Y F, Chu C M. Hepatitis B virus infection. Lancet 2009 Feb. 14; 373(9663): 582-592). It is reported that there are about 2 billion persons infected by HBV, and there are about 350 million persons infected with chronic HBV in the whole world now. Among these infected persons, the risk of finally dying of liver diseases associated with HBV infection reaches up to 15%-25%, and more than 1 million persons die of these diseases every year in the whole world (Dienstag J L., vide supra; and Liaw Y F et al., vide supra).
The therapeutic agents for chronic HBV infection now may be divided mainly into Interferons (IFNs) and nucleoside or nucleotide analogues (NAs) (Dienstag J L., vide supra; Kwon H, Lok A S. Hepatitis B therapy. Nat Rev Gastroenterol Hepatol 2011 May; 8(5): 275-284; and Liaw Y F et al., vide supra). The former includes common interferon (IFN) and Peg-interferon (Peg-IFN), which achieve the effect of inhibiting HBV and treating CHB mainly by enhancing the overall immunocompetennce in patients; the latter mainly includes lamivudine (LMV), adefovir dipivoxil (ADV), Entecavir (ETV), Telbivudine (LdT) and Tenofovir, which inhibit the HBV replication mainly by directly inhibiting polymerase activity of HBV. For HBV infected persons (e.g, CHB patients), said agents alone or in combination have already effectively inhibited virus replication in vivo, and greatly reduced HBV DNA level; in particular, after such a treatment for 52 weeks or longer, response rate that HBV DNA level was lower than the detection limit (virological response) in patients reached 40-80% (Kwon H et al., vide supra). However, the treatment with said agents alone or in combination cannot completely clear up HBV viruses in infected persons, and the response rate of the negative conversion ratio of HBsAg or HBsAg serological conversion (a marker indicative of complete clearance of HBV viruses in patients) is generally lower than 5% (Kwon H et al., vide supra). Therefore, it is urgent and necessary to develop novel therapeutic methods and agents capable of more effectively clearing up HBV viruses, particularly clearing up HBsAg for HBV infected patients.
It is one of the important research directions in this field to develop new agents for treating chronic HBV infection based on immunological means. Immunotherapy of chronic HBV infection is generally performed in two manners, i.e. passive immunotherapy (corresponding to medicaments in the form of antibodies, etc.) and active immunotherapy (corresponding to medicaments in the form of vaccines, etc.). Passive immunotherapy (with antibody as an example) refers to the process of administering a therapeutic antibody to a HBV infected patient and preventing naïve hepatocytes from HBV infection by virtue of antibody-mediated virus neutralization, or clearing up viruses and infected hepatocytes in vivo by virtue of antibody-mediated immune clearance, thereby achieving a therapeutic effect. Now, Anti-HBs polyclonal antibodies, obtained from serum/plasma of responder immunized with hepatitis B vaccine or rehabilitee of HBV infection, i.e. high-titer hepatis B immunoglobulin (HBIG), have been widely applied to blockage of mother-infant vertical transmission of HBV, prevention of chronic HBV infected patient from HBV re-infection after liver transplantation, and prevention of people accidently exposed to HBV from infection. However, the therapy concerning direct administration of HBIG to HBV-infected patients (e.g., CHB patients) has no significant therapeutic effect, and HBIG is restricted in many aspects such as relatively few sources of high-titer plasma, high cost, unstable property, and potential security problems. Active immunotherapy refers to the process of administering therapeutic vaccines (including protein vaccines, polypeptide vaccines, nucleic acid vaccines, etc.), stimulating chronic HBV-infected organism to raise cellular immunologic response (CTL effect, etc.) or/and humoral immunologic response (antibodies, etc.) to HBV, thereby achieving the purpose of inhibiting or clearing HBV. Now, there are no agents/vaccines for active immunotherapy that are definitely effective and are useful for treating chronic HBV infection yet.
Therefore, it is urgent and necessary to develop novel therapeutic methods and agents capable of more effectively treating HBV infection for HBV infected patients.